Kelvin C. Luk
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View article: Synphilin-1 modulates alpha-synuclein assembly, release and uptake
Synphilin-1 modulates alpha-synuclein assembly, release and uptake Open
Alpha-synuclein (aSyn) is an intrinsically disordered protein involved in phase separation and several age-associated neurodegenerative disorders, including Parkinson’s disease. However, its function and pathological role remain elusive. H…
View article: Human microglia reduce alpha-synuclein aggregation and are neuroprotective in adult mouse brain
Human microglia reduce alpha-synuclein aggregation and are neuroprotective in adult mouse brain Open
Microglia, brain-resident immune cells, are involved in pathophysiology of several neurodegenerative diseases, including Parkinson's disease. Given significant species-specific differences in microglia gene expression, particularly in dise…
View article: Blood α‐Synuclein Separates Parkinson's Disease from Dementia with Lewy Bodies
Blood α‐Synuclein Separates Parkinson's Disease from Dementia with Lewy Bodies Open
Objective Aggregation of misfolded α‐synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBDs), including Parkinson's disease (PD), and dementia with Lewy bodies (DLB) disease. Although evidence exists for a…
View article: Intrastriatal injection of alpha-synuclein preformed fibrils to rats results in L-DOPA reversible sensorimotor impairments and alterations in non-motor function
Intrastriatal injection of alpha-synuclein preformed fibrils to rats results in L-DOPA reversible sensorimotor impairments and alterations in non-motor function Open
Introduction The alpha-synuclein ( α -syn) preformed fibril (PFF) model of Parkinson’s disease (PD) is widely used in rodents to understand the mechanisms contributing to progression of pathology and neurodegeneration in the disorder. Whil…
View article: GDNF reduces fibril-induced early-stage alpha-synuclein pathology after delivery of 20S proteasome inhibitor lactacystin
GDNF reduces fibril-induced early-stage alpha-synuclein pathology after delivery of 20S proteasome inhibitor lactacystin Open
Failures in protein homeostasis are linked to Parkinson's disease (PD) and other neurodegenerative diseases. Lewy bodies, proteinaceous inclusions rich in phosphorylated alpha-synuclein are a hallmark of PD. Glial cell line-derived neurotr…
View article: Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease
Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease Open
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, α-Synuclein (α-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCI…
View article: Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions
Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions Open
The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed sc…
View article: NERINE reveals rare variant associations in gene networks across phenotypes and implicates an <i>SNCA-PRL-LRRK2</i> subnetwork in Parkinson’s disease
NERINE reveals rare variant associations in gene networks across phenotypes and implicates an <i>SNCA-PRL-LRRK2</i> subnetwork in Parkinson’s disease Open
There are two primary approaches to study the genetic basis of human phenotypes. Experiments in model systems generate interpretable gene networks but, in isolation, do not establish relevance to the human condition. Statistical genetics i…
View article: Glycine-to-aspartic acid mutation at codon 51 in <i>Snca</i> disrupts the synaptic localisation of α-synuclein and enhances its propensity for synucleinopathy
Glycine-to-aspartic acid mutation at codon 51 in <i>Snca</i> disrupts the synaptic localisation of α-synuclein and enhances its propensity for synucleinopathy Open
Point mutations in the SNCA gene, which encodes α-synuclein (αSyn), are a known cause of familial Parkinson’s disease. The glycine-51-aspartic acid (G51D) mutation causes early-onset neurodegeneration with complex, wide-spread αSyn patholo…
View article: Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn+PFFs-induced rat model for Parkinson’s disease
Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn+PFFs-induced rat model for Parkinson’s disease Open
Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration, α-Synuclein (α-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCI…
View article: Uptake of alpha‐synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia
Uptake of alpha‐synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia Open
Microglia are brain resident immune cells that maintain proteostasis and cellular homeostasis. Recent findings suggest that microglia dysfunction could contribute to the pathogenesis of Parkinson's disease (PD). One of the hallmarks of PD …
View article: Alpha-Synuclein Conformations in Plasma Distinguish Parkinson’s Disease from Dementia with Lewy Bodies
Alpha-Synuclein Conformations in Plasma Distinguish Parkinson’s Disease from Dementia with Lewy Bodies Open
View article: Current insights and assumptions on α-synuclein in Lewy body disease
Current insights and assumptions on α-synuclein in Lewy body disease Open
View article: Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions
Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions Open
The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed sc…
View article: Are Preformed Fibrils a Model of Parkinson’s Disease?
Are Preformed Fibrils a Model of Parkinson’s Disease? Open
Pre-formed fibrils (PFFs) made from recombinant α-synuclein are broadly used throughout the field in cellular and animal models of Parkinson’s disease. However, their ability to successfully recapitulate disease biology is a controversial …
View article: <i>Ciita</i> Regulates Local and Systemic Immune Responses in a Combined rAAV-<i>α</i>-synuclein and Preformed Fibril-Induced Rat Model for Parkinson’s Disease
<i>Ciita</i> Regulates Local and Systemic Immune Responses in a Combined rAAV-<i>α</i>-synuclein and Preformed Fibril-Induced Rat Model for Parkinson’s Disease Open
Background: Parkinson’s disease (PD) is characterized by alpha-synuclein ( α-Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen ( HLA) variants associated with PD and α-Syn specific CD4+ T lymphocytes in PD pa…
View article: α-Synuclein Conformations in Plasma Distinguish Parkinson’s Disease from Dementia with Lewy Bodies
α-Synuclein Conformations in Plasma Distinguish Parkinson’s Disease from Dementia with Lewy Bodies Open
Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn…
View article: Positron Emission Tomography with [18F]ROStrace Reveals Progressive Elevations in Oxidative Stress in a Mouse Model of Alpha-Synucleinopathy
Positron Emission Tomography with [18F]ROStrace Reveals Progressive Elevations in Oxidative Stress in a Mouse Model of Alpha-Synucleinopathy Open
The synucleinopathies are a diverse group of neurodegenerative disorders characterized by the accumulation of aggregated alpha-synuclein (aSyn) in vulnerable populations of brain cells. Oxidative stress is both a cause and a consequence of…
View article: Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia
Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia Open
Microglia are brain resident immune cells that maintain proteostasis and cellular homeostasis. Recent findings suggest that microglia dysfunction could contribute to the pathogenesis of Parkinson’s disease. One of the hallmarks of Parkinso…
View article: Alpha-synuclein inclusion responsive microglia are resistant to CSF1R inhibition
Alpha-synuclein inclusion responsive microglia are resistant to CSF1R inhibition Open
View article: Engineered Nanobodies With Programmable Target Antigen Proteolysis (Ptap) Fusions Regulate Intracellular Alpha-synuclein in Vitro and in Vivo
Engineered Nanobodies With Programmable Target Antigen Proteolysis (Ptap) Fusions Regulate Intracellular Alpha-synuclein in Vitro and in Vivo Open
Alpha-synuclein (αSyn) aggregation and the formation of Lewy pathology (LP) is a foundational pathophysiological phenomenon in synucleinopathies. Delivering therapeutic single-chain and single-domain antibodies that bind pathogenic targets…
View article: Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia
Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia Open
Microglia are brain resident immune cells and maintain proteostasis and cellular homeostasis there. Recent findings suggest that microglia dysfunction could contribute to the pathogenesis of Parkinson’s disease. One of the hallmarks of Par…
View article: MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons
MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons Open
View article: Author Correction: O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology
Author Correction: O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology Open
View article: O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology
O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology Open
View article: Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons
Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons Open
Alpha-synuclein (αSyn) protein levels correlate with the risk and severity of Parkinson’s disease and related neurodegenerative diseases. Lowering αSyn is being actively investigated as a therapeutic modality. Here, we systematically map t…
View article: Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease
Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease Open
Objective Alzheimer's disease neuropathologic change and alpha‐synucleinopathy commonly co‐exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test t…
View article: Neuroinflammatory gene expression profiles of reactive glia in the substantia nigra suggest a multidimensional immune response to alpha synuclein inclusions
Neuroinflammatory gene expression profiles of reactive glia in the substantia nigra suggest a multidimensional immune response to alpha synuclein inclusions Open
Parkinson's disease (PD) pathology is characterized by alpha-synuclein (α-syn) aggregates, degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc), and neuroinflammation. The presence of reactive glia correlates with …
View article: Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils
Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils Open
Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-s…
View article: Combining fibril‐induced alpha‐synuclein aggregation and 6‐hydroxydopamine in a mouse model of Parkinson's disease and the effect of cerebral dopamine neurotrophic factor on the induced neurodegeneration
Combining fibril‐induced alpha‐synuclein aggregation and 6‐hydroxydopamine in a mouse model of Parkinson's disease and the effect of cerebral dopamine neurotrophic factor on the induced neurodegeneration Open
The existent pre‐clinical models of Parkinson's disease do not simultaneously recapitulate severe degeneration of dopamine neurons and the occurrence of alpha‐synuclein (aSyn) aggregation in one study system. In this study, we injected aSy…